Fast Forward Therapeutic Innovation
Green tea is a significant source of a type of flavonoids called catechins including the most abundant epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG), and epicatechin (EC). There has been growing interest in catechins since it has been suggested they have several important pharmacological activities. We are interested in exploiting this class of natural products for a series of important diseases:
Hyperinsulinemia-Hyperammonemia Syndrome (HHS)
HHS is a rare autosomal dominant disease manifested by hypoglycemic symptoms triggered by fasting or high-protein meals, and by elevated serum ammonia. It is the second most common cause of hyperinsulinemic hypoglycemia in infancy. It is a rare genetic disease (prevalence is estimated at 1 in 200,000 new born/yr) caused by activating mutations in GLUD1, a gene located on chromosome 10q23.3., composed of 13 exons that encode the mitochondrial enzyme glutamate dehydrogenase (GDH). HHS has profound effects on several major organs. In the pancreas, dysregulated GDH causes an exaggerated insulin response to amino acid stimulation, leading to hypoglycemia. In the CNS, there is a high correlation between HHS and childhood-onset epilepsy, learning disabilities, and seizures that are independent of the high ammonium, low glucose serum levels.
The most promising lead compounds in the treatment for HHS are catechin derivatives found in green tea namely EGCG and ECG which inhibits GDH activity by binding to the ADP allosteric site in the enzyme [ref]. Avanti’s objective is to improve the pharmacokinetic properties of these natural products while maintaining their strong inhibitory activity for GDH by modifying their chemical scaffold.
Down Syndrome (DS)
DS is a genetically complex disorder characterized by systemic phenotypes including mental retardation, cardiovascular anomalies, craniofacial dysmorphology, malignant neoplasms such as acute myoblastic leukemia, and recurrent infections. DS involves the potential deregulation of every gene on chromosome 21 and perturbation of innumerable pathways directly or indirectly tied to these genes. The protein kinase DYRK1A (dual-specificity tyrosine-phosphorylation regulated kinase) is increasing being viewed as a major contributor to the etiology of the disease as well as a viable target for therapeutic intervention. DYRK1A phosphorylates exogenous substrates on serine/threonine residues, and autophosphorylates an essential tyrosine in the activation loop region of the kinase domain. Autophosphorylation is an intramolecular co-translational event mediated by a short-lived intermediate that is essential for full catalytic activity.
DYRK1A is highly conserved both in sequence and function (human and mice display 99% sequence identity). Model organism- as well as human-based studies provides compelling evidence that DYRK1A plays an essential role in neurogenesis and development of the brain, a role conserved from fruit flies to humans. EGCG was identified as an inhibitor of DYRK1A with an IC50 value of 330 nM. EGCG has been shown in mouse models to rescue cognitive deficits associated with overexpression of DYRK1A on its own as well as rescue of mouse models of DS. Studies by De la Torre using green tea extract showed that he was able to rescue the cognitive deficits of both segmental trisomy 16 (Ts65Dn) and transgenic mice overexpressing DYRK1A. Furthermore, green tea extracts was safe and reversed cognitive deficits in a randomized, double-blind placebo-controlled in a phase 1 trial study in young individuals with Down’s syndrome. More recently, results from a phase 2 clinical trial using green tea (equivalent to ~10mg/kg/d of EGCG for 12 months) in young adults with DS showed that treatment group was significantly more effective than placebo and cognitive training at improving visual recognition memory, inhibitory control, and adaptive behaviour [ref].
Alzheimer's Disease (AD)
Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative disease that insidiously and relentlessly destroys memory and other cognitive abilities. AD is characterized by the presence of intraneuronal neurofibrillary tangles (NFT) of hyperphosphorylated microtubule-associated protein tau and extraneuronal neuritic plaques primarily composed of amyloid β-42 (Aβ42). NFT and β-amyloid plaques are the two pathological hallmarks of the disease.
Tau hyperphosphorylation triggers synaptic dysfunction and formation of neurofibrillary tangles (NFTs), both of which feature in the pathogenesis of Alzheimer’s disease. Treatments that reduce tau phosphorylation are hypothesized to block and potentially reverse pathogenesis and disease progression. Avanti Biosciences is pioneering the development of potent negative allosteric modulators of DYRK1A, a kinase that phosphorylates tau and whose activity is believed to be linked to p-tau mediated synaptic and neuronal dysfunction and death in AD [ref]. In collaboration with NY Institute for Basic Research, Avanti has identified catechins that negatively modulate the activity of DYRK1A, suggesting that potent allosteric inhibition of DYRK1A can be achieved.
